This invention relates to biologically active vitamin D.sub.3 compounds. More specifically, the invention relates to 19-nor-analogs of 1.alpha.,25-hydroxylated vitamin D.sub.3 compounds having calcemic activity.
The 1.alpha.-hydroxylated metabolites of vitamin D--most importantly 1.alpha.,25-dihydroxyvitamin D.sub.3 and 1.alpha.,25-dihydroxyvitamin D.sub.2 --are known as highly potent regulators of calcium homeostasis in animals and humans, and their activity in cellular differentiation has also been established. V. Ostrem et al, Proc. Natl. Acad. Sci. USA, (1987), 84, 2610. As a consequence, many structural analogs of these metabolites, such as compounds with different side chain structures, different hydroxylation patterns, or different stereochemistry, have been prepared and tested. Important examples of such analogs are 1.alpha.-hydroxyvitamin D.sub.3, 1.alpha.-hydroxyvitamin D.sub.2, various side chain fluorinated derivatives of 1.alpha.,25-dihydroxyvitamin D.sub.3, and side chain homologated analogs. Several of these known compounds exhibit highly potent activity in vivo or in vitro, and some of these have been found to exhibit an interesting separation of activities in cell differentiation and calcium regulation. This difference in activity provides these compounds with advantageous therapeutic activity profiles and thus numerous of these compounds are in use, or have been proposed for use, in the treatment of a variety of diseases such as renal osteodystrophy, vitamin D-resistant rickets, osteoporosis, psoriasis, and certain malignancies.
Recently, a new class of vitamin D analogs has been discovered, i.e. the so-called 19-nor-vitamin D compounds. 19-Nor-vitamin D compounds are vitamin D analogs in which the ring A exocyclic methylene group (carbon 19) typical of all vitamin D compounds has been removed and replaced by two hydrogen atoms. Specifically, these compounds were reported to exhibit a selective activity profile with high potency in inducing cellular differentiation, and minimal bone calcification activity. See U.S. Pat. No. 5,587,497. Such a differential activity profile renders these compounds useful for the treatment of malignancies, or the treatment of various skin disorders such as psoriasis. Several different methods of synthesis of these 19-nor-vitamin D analogs have been described (Perlman et al. Tetrahedron Letters 31, 1823 (1990); Perlman et al Tetrahedron Letters 32, 7663 (1991); and DeLuca et al U.S. Pat. No. 5,086,191).
In a continuing effort to explore the new 19-nor class of pharmacologically important vitamin D analogs, the 19-nor-26,27-dihomo-1.alpha.,25-(OH).sub.2 D.sub.3 and the 19-nor-26,27-dihomo-22,23(E)-1.alpha.,25-(OH).sub.2 D.sub.3 analogs of 19-nor-1.alpha.,25-dihydroxyvitamin D.sub.3 have now been synthesized. The two 26,27 homologated analogs showed relatively high in vivo calcemic activity, i.e. calcium transport activity and bone calcium mobilization activity. Both analogs also induced differentiation of HL-60 cells. These two analogs as well as other 26 and/or 27 homologated 19-nor compounds disclosed hereinafter thus show promise in the treatment of osteoporosis.